Preclinical proof of principle for orally delivered Th17 antagonist miniproteins

  • Cell. 2024 Aug 8;187(16):4305-4317.e18. doi: 10.1016/j.cell.2024.05.052.
Stephanie Berger  1 ,  Franziska Seeger  2 ,  Ta-Yi Yu  3 ,  Merve Aydin  4 ,  Huilin Yang  5 ,  Daniel Rosenblum  6 ,  Laure Guenin-Macé  7 ,  Caleb Glassman  8 ,  Lauren Arguinchona  2 ,  Catherine Sniezek  9 ,  Alyssa Blackstone  9 ,  Lauren Carter  9 ,  Rashmi Ravichandran  9 ,  Maggie Ahlrichs  9 ,  Michael Murphy  9 ,  Ingrid Swanson Pultz  9 ,  Alex Kang  2 ,  Asim K Bera  2 ,  Lance Stewart  9 ,  K Christopher Garcia  10 ,  Shruti Naik  11 ,  Jamie B Spangler  12 ,  Florian Beigel  13 ,  Matthias Siebeck  4 ,  Roswitha Gropp  4 ,  David Baker  14
Affiliations
  • 1. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected].
  • 2. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • 3. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
  • 4. Department of General, Visceral and Transplantation Surgery, LMU University Hospital, LMU Munich, 81377 Munich, Germany.
  • 5. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD 21231, USA.
  • 6. Department of Pathology, NYU Langone Health, New York, NY 10016, USA.
  • 7. Department of Pathology, NYU Langone Health, New York, NY 10016, USA; Immunobiology and Therapy Unit, INSERM U1224, Institut Pasteur, Paris 75015, France.
  • 8. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94304, USA.
  • 9. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • 10. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94304, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94304, USA; Howard Hughes Medical Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • 11. Department of Pathology, NYU Langone Health, New York, NY 10016, USA; Department of Medicine, Ronald O. Perelman Department of Dermatology, Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA.
  • 12. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD 21231, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
  • 13. Department of Medicine II, LMU University Hospital, LMU Munich, 80336 Munich, Germany.
  • 14. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected].
PMID: 38936360 DOI: 10.1016/j.cell.2024.05.052
Abstract

Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.

Keywords
IL-17; IL-23R; Th17; autoinflammation; computational protein design; inflammatory bowel disease; oral biologics; protein engineering.
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